This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Previous studies have demonstrated that immunization with SIVdeltanef results in partial protection against IV challenge with SIVmac251 at 5 weeks after immunization but complete protection by 15 weeks. These results suggest that detailed analysis of the ontogeny of immune responses after infection with SIVdeltanef should offer insights into the mechanisms of protective immunity. We undertook a comprehensive analysis of the ontogeny of SIV-specific immune responses induced by SIVdeltanef and the correlation of these responses to protection against intravenous challenge with SIVmac239. Relatively high frequency SIV-specific T cell responses were detected as early as 2 weeks after SIVdeltanef infection. Longitudinal analysis demonstrated ELISPOT responses had decayed by approximately one-third 14 weeks after infection, with no apparent broadening of the cellular immune response. Challenge of these animals with an intravenous dose of SIVmac239 at 5 and 15 weeks after infection revealed apparently sterile protection in all animals, with no wild-type plasma viremia detectable and expected high viral loads in unvaccinated controls. Analysis of whole proteome ELISPOT responses and tetramer responses revealed no evidence of anamnestic CD8-positive T cell responses in vaccinated animals following challenge at either 5 or 15 weeks. These data demonstrate that protection against homologous protection with SIVmac239 can occur as early as 5 weeks after SIVdeltanef infection and that the previously observed maturation of protection against SIVmac251 does not appear to correlate with quantitative changes in SIV-specific CD8-positive T cell responses.